Summary of Work: AIDS research into the cellular mechanisms of lymphocyte and neuronal damage by HIV infection has been revolutionized in the past few years by the report that chemokine receptors are coreceptors for HIV infection of T lymphocytes and macrophages. Chemokine receptors act through the same pertussis toxin sensitive G proteins we have studied in pituitary and heart. In addition potassium channels have been implicated directly in apoptosis in lymphocytes and neurons. Microglia are macrophage like cells in the CNS that respond to neuronal damage by releasing proinflammatory cytokines. Although subsequent work has verified and extended these studies, very little is known about the signal transduction mechanisms mediating the effects of chemokine receptor activation on microglial function.Therefore, we are investigating the mechanism of potassium channel regulation by chemokines, its disruption by gp120, and its consequences for microglial and neuronal cell death. In the past year we have identified a molecular cascade linking death receptors to stimulation of a specific class of potassium channel in a human T lymphocyte cell line, which involves FADD and caspase 8 but not caspase 3, and is reversed by PKC stimulation. In addition we have demonstrated that chemokines regulate the activity of similar potassium channels in microglia cells isolated acutely from embryonic mouse brain.